Age-related neurodegenerative diseases including Alzheimer's disease (AD) and Huntington's disease (HD) are associated with mild impairment of oxidative metabolism, oxidative stress and accumulation of abnormal proteins. The underlying hypothesis of this program project is that mitochondrial dysfunction in age-related neurodegenerative diseases promotes the development of disease and impairs the ability of the brain to adapt. The four project leaders have career long commitments to understanding the role of mitochondria and oxidative stress in normal and diseased brains with the goal of developing new therapies. Plausible mechanisms link the disease related mitochondrial abnormalities to the pathophysiology. Thus, an understanding of the causative (i.e., upstream events) as well as consequences (i.e. downstream events) of the mitochondrial change will help develop new therapeutic strategies. Our results in human brains at autopsy in numerous age-related neurodegenerative diseases reveal decreased activity of the mitochondrial enzyme a- ketoglutarate dehydrogenase complex (KGHDC) and an increased activity of transglutaminase (TGase). KGDHC is arguably the rate limiting step for NADH formations, produces ROS, is obligatory for heme production, and is very sensitive to oxidants. TGase is a cross linking enzymes that can modulate transcription, inactivate metabolic enzymes, and cause aggregation of critical proteins. Our recent data indicate that TGase can silence expression of genes involved in compensating for metabolic stress. The events upstream of these enzyme changes will be explored by testing for post-translational modification of enzymes and abnormal oxidant production in mitochondria from autopsy brains. Whether the consequences of the disease associated changes in TGase and KGDHC are protective or damaging is unclear. Therefore, the downstream consequences and therapeutic strategies will be tested at multiple levels of biological complexity: isolated proteins, gene transcription, cultured cells, fruit flies and transgenic mice. The proposed experiments will test whether increasing KGDHC via inhibition of TGase or via a host of other strategies would be effective therapeutic approaches in age-associated neurodegenerative diseases. Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations.